PROJECT SUMMARY Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that is characterized by pathogenic autoantibody production and is associated with prevalent hypertension, renal injury, and cardiovascular disease. Our laboratory has shown that female NZBWF1 mice, an established mouse model of SLE, develop hypertension and exhibit impaired renal hemodynamic function, including increased renal vascular resistance and impaired renal sodium excretion. Recent studies by our laboratory have shown that chronic B cell depletion with anti-CD20 monoclonal antibody reduces autoantibody production and prevents the development of hypertension; however, the treatment was only effective when administered before the onset of autoantibody production. Additional preliminary data indicates that treatment with the immunosuppressive drug mycophenolate mofetil (MMF) resulted in B cell depletion, lowered anti-dsDNA autoantibody production, and attenuation of hypertension. While these data support the concept that autoreactive B cells and the associated autoantibodies contribute to SLE hypertension, it is important to recognize that the majority of serum immunoglobulin is secreted by long-lived plasma cells that are differentiated from B cells and not affected by either MMF or anti-CD20 therapies. Initial studies with the proteasome inhibitor bortezomib reveal that this drug depletes plasma cells and lowers autoantibody production in NZBWF1 mice. Based on these preliminary data, my central hypothesis is that pathogenic autoantibodies produced by plasma cells during SLE impair renal hemodynamic function, causing a shift in the pressure natriuresis relationship, resulting in the development of hypertension. Aim 1 of the proposal will test the hypothesis that production of autoantibodies by plasma cells promotes the development of hypertension during SLE and aim 2 will test the hypothesis that autoantibodies impair renal hemodynamic function causing a hypertensive shift in the pressure natriuresis relationship. The proposed studies have clinical relevance because they examine the link between autoantibody production and the development of hypertension in SLE, which may help to improve therapies for these patients. Furthermore, the presence of pathogenic autoantibodies in essential hypertension; thus, studies aimed at understanding the mechanistic role that autoantibodies have in hypertension may have broad implications for blood pressure control in multiple patient populations.